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A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives were optimized to achieve potent agonistic activity, both in vitro and in vivo, for the arginine vasopressin V(2) receptor, resulting in the eventual discovery of compound 1g. Molecular modeling of compound 1g with V(2) receptor was also examined to evaluate the binding mode of this series of compounds.

Aims Nociceptive behavior and its relationship with bladder dysfunction were investigated in two cystitis models, which were induced by intraperitoneal (ip) injection of cyclophosphamide (CYP) or intravesical instillation of acetone, using freely moving, non-catheterized conscious rats.

A series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives was synthesized, and their structure-activity relationships were examined in order to identify potent and selective arginine vasopressin V(2) receptor agonists. Attempts to substitute other chemical groups in place of the 2-pyridilmethyl moiety of 1a led to the discovery that potent V(2) binding affinity could be obtained with a wide range of functional groups. This structural tolerance allowed for the manipulation of other attributes, such as selectivity against V(1a) receptor affinity or avoidance of the undesirable inhibition of cytochrome P450 (CYP), without losing potent affinity for the V(2) receptor. Some representative compounds obtained in this study were also found to decrease urine volume in awake rats.

We investigated the effect of tamsulosin, an alpha(1)-adrenoceptor antagonist, on bladder function, especially spontaneous bladder contractions before micturition (premicturition contraction), in conscious rats with bladder outlet obstruction induced by partial urethral ligation, and compared the results with the effect on intraurethral pressure response in anesthetized rats. In obstructed rats, the alpha(1)-adrenoceptor antagonists tamsulosin, naftopidil and urapidil and non-selective alpha-adrenoceptor antagonist phentolamine inhibited premicturition contractions in a dose-dependent fashion. In contrast, yohimbine, an alpha(2)-adrenoceptor antagonist, and atropine, a muscarinic receptor antagonist, hardly inhibited them. Tamsulosin and urapidil showed clearly inhibitory effects on increases in intraurethral pressure induced by phenylephrine, an alpha(1)-adrenoceptor agonist, in the same dose range as that at which they inhibited premicturition contractions, whereas naftopidil required somewhat higher doses to inhibit increases in intraurethral pressure than those at which it inhibited premicturition contractions. In conclusion, premicturition contractions observed in obstructed rats were sensitive to alpha(1)-adrenoceptor antagonists, but not to alpha(2)-adrenoceptor or muscarinic receptor antagonists. Tamsulosin was shown to be effective against both premicturition contraction and intraurethral pressure response in the same dose range in rats. These results partly support the fact that tamsulosin has improved storage symptoms as well as voiding symptoms in patients with lower urinary tract symptoms associated with bladder outlet obstruction by blocking alpha(1)-adrenoceptors.

The aim of the present study was to investigate the effects of tamsulosin, an α 1 -adrenoceptor antagonist, on hypogastric nerve stimulation-induced intraurethral pressure elevation in anesthetized male and female dogs and to evaluate sex differences in these effects. Additionally, the effects of tamsulosin were also compared with those of other α 1 -adrenoceptor antagonists, namely prazosin, naftopidil and urapidil. Tamsulosin dose-dependently inhibited hypogastric nerve stimulation-induced intraurethral pressure elevation, with doses required to induce 50% inhibition of the elevation (ED 50 values) of 0.72 and 0.74 μg/kg i.v. in anesthetized male and female dogs, respectively. Mean arterial blood pressure slightly decreased after administration of tamsulosin at a dose which inhibited intraurethral pressure elevation almost completely. Prazosin, naftopidil and urapidil also inhibited increases in intraurethral pressure in a dose-dependent fashion, but caused decreases in mean arterial blood pressure at the same doses. The estimated rank order of inhibitory potency for urethral response was tamsulosin>prazosin>naftopidil=urapidil. In conclusion, tamsulosin dose-dependently inhibited increases in intraurethral pressure with little effect on mean arterial blood pressure in both male and female dogs, and these effects were almost equipotent. These results indicate that tamsulosin will be useful in the treatment of dysuria associated with lower urinary tract symptoms in women as well as men.

The detrusor muscle contains β-adrenoceptors (β-AR) and three subtypes, such as β1-AR, β2-AR, and β3-AR, which have been identified in most species. There is a predominant expression of β3-AR messenger RNA in human bladder tissue when compared with the β1-AR and β2-AR subtypes. Moreover, the presence of β1, β2, and β3-AR in the human urothelium has been identified. It has also been demonstrated in animals that relaxation mediated through βs-AR is achieved solely by cAMP-dependent mechanisms in non-contracted detrusor muscles, whereas in KCl precontracted detrusor muscles, cAMP-dependent and -independent mechanisms by way of calcium-activated K +(BK Ca) channels may be involved in β-adrenergic relaxation. In addition, a recent phase II proof-of-concept study using a novel selective β3-adrenoceptor agonist (YM178) has shown clinical efficacy in the treatment of overactive bladder (OAB) symptoms, suggesting that β3-AR should be used as a therapeutic target for the treatment of OAB disorders.

YM934 is a novel synthetic potassium-channel opener. We have investigated its anti-asthma effect after intravenous (i.v.) and oral (p.o.) administration in various experimental asthma models in the guinea-pig, and compared the results with those for lemakalim, theophylline and salbutamol. In an ovalbumin-active sensitization anaphylaxis asthma model, YM934, lemakalim, theophylline and salbutamol dose-dependently prolonged the time before the occurrence of asthma attacks and reduced the mortality rate. The respective ED50 values (dose required to prolong by 50% the time before the occurrence of attacks) of the anti-asthma effects of YM934, lemakalim, theophylline and salbutamol were 6, 340, 30 000, and 45 μg kg−1 (i.v.); the efficacy ratios were YM934 (1) > salbutamol (1/9) > lemakalim (1/57) » theophylline (1/5000). YM934 also prolonged the period before the occurrence of attacks in the anti-BSA (bovine serum albumin) serum-passive sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values for these models of 15, 22 and 20 μg kg−1 (i.v.). Among these models a reduction in mortality rate was seen in the histamine- and methacholine-induced asthma models. After oral administration, YM934 showed an anti-asthma effect in the ovalbumin-active sensitization anaphylaxis, histamine-induced and methacholine-induced asthma models, with respective ED50 values of 38, 44 and 193 μg kg−1. YM934 was 5–6 times more potent than salbutamol. These results indicate that YM934 has potent anti-asthma activity, and that this activity is mainly attributable to bronchodilation, most likely mediated through its potassium-channel opening activity.

The present work describes the discovery of novel series of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene)acetamide derivatives as arginine vasopressin (AVP) V(2) receptor agonists. By replacing the amide juncture in YM-35278 with a direct ring connection gave compound 10a, which acts as a V(2) receptor agonist. These studies provided the potent, orally active non-peptidic V(2) receptor agonists 10a and 10j.

A new animal model in which to concurrently evaluate bladder function and nociceptive behavior was developed using freely moving, noncatheterized, conscious rats to assess the nociceptive behavior responses induced by intravesical instillation of resiniferatoxin (Sigma) and its relationship with bladder dysfunction.In female Sprague-Dawley rats resiniferatoxin (0, 0.3 and 3 microM) was instilled via a catheter that was temporarily inserted into the bladder through the urethra. After removing the catheter the incidence of nociceptive behavior (lower abdominal licking and freezing) was scored. Voided urine was collected continuously to measure bladder capacity. In some rats the pudendal nerves were transected bilaterally to eliminate the activation of urethral afferents by resiniferatoxin.Intravesical instillation of resiniferatoxin induced decreased bladder capacity and increased nociceptive behaviors, such as licking and freezing, which were blocked by the transient receptor potential vanilloid receptor 1 antagonist BCTC (Biomol). In rats with pudendal nerve transection the early phase of resiniferatoxin induced licking was decreased without affecting the resiniferatoxin induced decrease in bladder capacity and late phase licking behavior. Resiniferatoxin induced late phase licking in the water unloaded group was observed to a lesser extent than in the water loaded diuresis group.The intravesical instillation of resiniferatoxin, which decreases bladder capacity, acts by at least 3 distinct mechanisms to induce licking behavior, including 1) an immediate response mediated by the activation of urethral afferents in the pudendal nerve, 2) a late response evoked by the direct stimulation of C-fiber afferents in the bladder and 3) gradual facilitation of the response elicited by the bladder wall distention induced by rapid bladder filling.

Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the antimuscarinic properties of solifenacin and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin, propiverine and atropine. In radioligand receptor binding assay, Ki values of solifenacin for human muscarinic M1, M2, M3, M4 and M5 receptors were 26, 170, 12, 110 and 31 nM, respectively. In isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pA2 value of 7.44+/-0.09. In these in vitro studies, the antimuscarinic action of solifenacin was more potent than that of propiverine and less potent than those of tolterodine, oxybutynin, darifenacin and atropine. In anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure. The dosages required to produce a 30% increase in maximum bladder capacity (ED30 values) of solifenacin and oxybutynin were 0.35 and 0.30 mg/kg i.v., respectively, indicating approximately equal efficacies. These results support the fact that solifenacin, similarly to currently used antimuscarinic agents, is an effective agent in the treatment of overactive bladder symptoms such as urinary frequency and urge incontinence.

The contractile responses to capsaicin and anandamide, exogenous and endogenous agonists for transient receptor potential vanilloid receptor 1 (TRPV1), respectively, were investigated in muscle strips isolated from the rat urinary bladder. Capsaicin and anandamide produced concentration-dependent contractions of the muscle strips. The contractile response induced by capsaicin disappeared within approximately 20 min. In contrast, anandamide produced contractile responses lasting at least for 30 min. Capsaicin produced additive contractile responses in anandamide-treated muscle strips. The contractile response to anandamide was attenuated, but not abolished in strips desensitized by capsaicin. The response to capsaicin was abolished in the presence of a TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chlorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), but not altered in the presence of either tetrodotoxin, atropine or indomethacin. In the presence of SR140333, a tachykinin NK(1) receptor antagonist or SR48968, an NK(2) receptor antagonist, the response to capsaicin was attenuated. The response to anandamide was partially attenuated in the presence of ONO8130, a prostanoid EP(1) receptor antagonist, URB597, a fatty-acid amide hydrolase inhibitor, BCTC, SR140333 or SR48968, and almost completely abolished by indomethacin. Neither tetrodotoxin, atropine, a cannabinoid CB(1) receptor antagonist, AM251, nor a cannabinoid CB(2) receptor antagonist, AM630, had any effect on the response to anandamide. These results indicate that capsaicin produces muscle contractions by stimulating the TRPV1 receptor, followed by release of neuropeptides that can activate tachykinin NK(1) and/or NK(2) receptors in the bladder and that the contractile response to anandamide is mediated at least in part by activation of prostanoid EP(1) receptors due to production of prostaglandins in addition to TRPV1 receptor activation.